Pharmaceutical Development of a New Class of Antibiotics Effective Against Anthrax
Abstract
The primary goal of this program was to identify and develop a novel compound with antibiotic activity against anthrax. We initially focused on the development of borinic acid esters. The early leads did not prove to have sufficient attributes to be developed as therapeutics. Efforts then focused on optimizing the compounds to possess better pharmacokinetics and lower protein binding. By May, 2004, compounds were synthesized with low protein binding, good bioavailability, long half lives and good tissue penetration. Unfortunately, in rodent anthrax models the best compound totally protected only 20% of the mice inoculated with a lethal anthrax dose. It was clear from these studies that a high volume of distribution was needed for in vivo efficacy. Based on this finding we focused instead on AN0900, a semisynthetic glycopeptide antibiotic with a very large volume of distribution that worked by inhibiting transglycosylase. Initial studies in both the intravascular vegetative anthrax and the pulmonary anthrax mouse models demonstrated that AN0900 administration 1 h after anthrax inoculation provided complete protection using a single daily dose of 10-25 mg/kg. In conclusion, within the 2 years of the contract, AN0900 was discovered and represents a novel compound working by a unique mechanism of action.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 15, 2004
- Accession Number
- ADA427487
Entities
People
- Kirk R. Maples